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Genome-Wide Polygenic Score Quantifies Inherited Susceptibility to Obesity

Key findings

  • By analyzing millions of sites of common DNA variations in the human genome, researchers have developed a polygenic score for obesity, a quantitative tool that predicts an individual's inherited risk for becoming overweight.
  • The genome-wide polygenic score (GPS) accurately predicted striking differences in weight, severe obesity, cardiometabolic diseases and overall mortality in middle-aged adults
  • The GPS was only minimally associated with birthweight, but it was strongly associated with a gradient in weight that started to emerge early in childhood and even larger differences in weight and severe obesity in subsequent decades

Severe obesity, defined as body mass index (BMI) ≥40 kg/m2, is often stigmatized because it is assumed to result primarily from poor diet and lack of physical activity. However, obesity is known to have an important inherited component as well.

In rare cases, inherited susceptibility to obesity is attributable to a single gene mutation that greatly disturbs energy homeostasis or fat deposition. For the vast majority of people, however, genetic susceptibility to severe obesity seems to be polygenic: it results from the cumulative effects of numerous DNA variants that individually have modest effects.

Amit V. Khera, MD, associate director of the Precision Medicine Unit at the Center for Genomics Medicine and cardiologist at Massachusetts General Hospital, Sekar Kathiresan, MD, director of the Center for Genomic Medicine, and colleagues created a robust polygenic predictor of BMI and obesity, and in Cell, they report that a single genome-wide polygenic score (GPS) was effective in identifying subsets of adults at risk of severe obesity.

Creating and Validating the GPS

To create the GPS, the researchers determined the average effects of each of 2.1 million genetic variants on BMI from the largest published genome-wide association study of obesity. Using a computational algorithm, they reweighted each variant according to the effect size and strength of statistical significance observed in the prior study, the degree of correlation between a variant and others nearby, and a "tuning parameter" that denoted the proportion of variants with non-zero effect.

The best choice of tuning parameter was difficult to know upfront, so the researchers tested five values. Each of the five candidate GPSs was strongly associated with the BMIs measured in 119,951 middle-aged participants in the U.K. Biobank.

The researchers selected the best score, which had a correlation coefficient of 0.29, and tested its ability to predict weight and BMI in 306,135 participants from four European cohorts.

Polygenic Susceptibility to Obesity in Middle Age

In a U.K. Biobank testing dataset of 288,016 middle-aged adults, the correlation of the GPS and BMI was 0.29, identical to the result in the validation dataset. Correlations were similar when participants were stratified into five-year age bands.

The researchers then stratified the population according to GPS deciles and found striking differences. For example:

  • Average weight: 187 lb for those in the top decile vs. 159 lb for those in the bottom decile, a difference of 28 lb
  • Obesity: 43% vs. 10%, a more than four-fold difference
  • Severe obesity: 5.6% vs. 0.2%, a 25-fold difference

High GPS, Extreme Obesity and Cardiometabolic Disease

Compared with participants in the other GPS deciles, those in the top decile had 4.2-, 6.6-, and 14.4-fold increased risk of BMI of ≥40, ≥50 and ≥60 kg/m2, respectively, and a five-fold increased risk of undergoing bariatric surgery. The risk of bariatric surgery was evaluated by combining participants from the U.K. Biobank and the Partners HealthCare System dataset of 6,536 adults.

Middle-aged adults in the U.K. Biobank who were in the top GPS decile were also at significantly increased risk of diabetes mellitus (by 72% compared with those in other deciles), venous thromboembolism (41%), coronary artery disease (28%), hypertension (38%), congestive heart failure (34%), ischemic stroke (23%) and death (19%).

Young Adults' Risk of Severe Obesity

The GPS predicted which individuals are at risk of developing severe obesity between young adulthood and middle age. This was determined using data on 3,722 young adults in the Framingham Offspring and Coronary Artery Risk Development in Young Adults studies. Among individuals in the top decile of the GPS, 16% developed severe obesity over a median follow-up period of 27 years, compared with 5.6% of those in all other deciles combined and 1.3% of those in the lowest decile.

Age of Emergence of Polygenic Susceptibility

By studying 7,861 participants in the Avon Longitudinal Study of Parents and Children, the researchers found that the effect of polygenic susceptibility to severe obesity emerges in childhood. The GPS was associated with only small differences in birth weight, but by age 8, the difference between children in the top and bottom deciles was 3.5 kg (P < .0001). By age 18, the difference was 12 kg (P < .0001).

Intriguingly, the latter difference was comparable to the 13 kg difference seen in the middle-aged participants in the U.K. Biobank.

Toward Targeted Interventions

Prior studies suggest that an unhealthy diet, physical activity and sedentary behavior affect BMI most in people who are genetically predisposed to obesity. The ability to identify high-risk individuals may facilitate prevention strategies that would have increased effect or cost-effectiveness, the researchers say. They suspect the interventions would have maximum impact if started early in life.

of middle-aged adults in the top decile of the genome-wide polygenic score (GPS) were obese

of young adults—none of whom were severely obese—in top GPS decile went on to develop severe obesity by middle age, compared with 1.3% in the bottom decile

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